Design, synthesis and characterizations of prodrugs of brexanolone.

A series of prodrugs of brexanolone, the synthetic version of the endogenously produced γ-aminobutyric acid A receptors positive allosteric modulator allopregnanolone, were designed, synthesized, and evaluated in vitro and in vivo. The effect of different function groups connecting to brexanolone C3 hydroxyl as well as those at the chain terminals of prodrug moieties were explored. Through these efforts, prodrugs that can efficiently release brexanolone in vitro and in vivo, and possess a potential for sustained delivery of a long acting brexanolone were discovered.

Human epidermal growth factor receptor 2 expression in mixed gastric carcinoma.

AIM: To investigate human epidermal growth factor receptor 2 (HER2) amplification and protein expression in mixed gastric carcinoma. METHODS: Fluorescence in situ hybridization and immunohistochemistry were used to detect HER2 amplification and protein expression in 277 cases of mixed gastric carcinoma. Protein staining intensity was rate as 1+, 2+, or 3+. RESULTS: Of the 277 cases, 114 (41.2%) expressed HER2 protein. HER2 3+ staining was observed in 28/277 (10.1%) cases, 2+ in 37/277 (13.4%) cases, and 1+ in 49/277 (17.7%) cases. A HER2 amplification rate of 17% was detected, of which 25/28 (89.3%) were observed in the HER2 3+ staining group, 17/37 (45.9%) in 2+, and 5/49 (10.2%) in 1+. Of the 47 patients with HER2 amplification who received chemotherapy plus trastuzumab, 22 demonstrated median progression-free and overall survivals of 9.1 mo and 16.7 mo, respectively, which were significantly better than those achieved with chemotherapy alone (5.6 mo and 12.1 mo, respectively) in 19 previously treated patients (Ps < 0.05). CONCLUSION: HER2 detection in mixed gastric carcinoma displays high heterogeneity. Relatively quantitative parameters are needed for assessing the level of HER2 amplification and protein expression.